1995 Fiscal Year Final Research Report Summary
Association of the functional impairement of T cells from patients with systemic lupus erythematosus with protein phosphorylation
| Project/Area Number |
05670424
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
内科学一般
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| Research Institution | Saga Medical School (1995)
Kyushu University (1993-1994) |
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Principal Investigator |
NAGASAWA Kohei Saga Medical School, Internal Medicine, Professor, 医学部, 教授 (00108721)
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| Co-Investigator(Kenkyū-buntansha) |
USHIYAMA Osamu Saga Medical School, Internal Medicine, Instructor, 医学部, 助手 (40253596)
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| Project Period (FY) |
1993 – 1995
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| Keywords | T cell activation / Phosphorylation / SLE / Protein kinase C / Okadaic acid / TNF-alpha / HTLV-1 / T cell-B cell interaction |
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| Research Abstract |
It had previously been found that T cells from patients with systemic lupus erythematosus (SLE) had an impaired proliferative response to phorbol myristate acetate (PMA). In this study we found that the phosphorylation of 80kDa and 64kDa proteins in T cells from SLE patients was markedly decreased in response to PMA,which was suggested to be responsible for the impaired activation of T cells from SLE patients. We, then, studied the effect of okadaic acid, an inhibitor of serine/threonine-specific protein phosphatase, in human T cell activation and phsphorylation of internal substrates. It was demonstrated that okadaic acid enhanced PMA-induced proliferation and CD25 (IL-2 receptor) expression in T cells. Moreover, preincubation with okadaic acid enhanced PMA-induced phosphorylation of the 80kDa protein, an internal substrate of protein kinase C in T cells. These effects of okadaic acid were reduced in T cells from SLE patients. These results suggested that the phosphorylation of some intracellular proteins was related to the T cell activation mediated by protein kinase C pathway.
Membrane tumor necrosis factor alpha (TNF-alpha) expressed on activated T cells has recently been demonstrated to play a role in T cell-B cell interaction. We found that normal human T cells, when infected with HTLV-1 in vitro, were induced to express 26kDa membrane TNF-alpha. The infected T cells activated autologous B cells to produce IgM through this molecule, which was inhibited by anti-TNF-alpha antibody. Anti-TNF-alpha antibody elicited the elevation of intracellular calcium concentration and induced the production of IL-2 and IFN-gamma in these HTLV-1-infected and membrane TNF-alpha-expressing T cells. These results suggest that the membrane TNF-alpha expressed on T cells is a novel functional molecule and its role in the pathogenesis of autoimmune diseases includig SLE and Sjogren's syndrome is now under investigation.
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